Influence of dithiocarbamates on the metabolism and toxicity of N-nitrosodimethylamine in rats.
Five secondary amines and secondary amino acids were reacted with carbon disulfide to yield dithiocarbamates. These compounds were tested for their influence on biochemical parameters and on some biological effects of N-nitrosodimethylamine (NDMA). The following results were found. (i) All dithiocarbamates tested reduced the activity of N-nitrosodiethylamine-deethylase and completely inhibited the N-nitrosodimethylamine-demethylase in the rat liver. A striking influence on the glutathione content and on the activity of glutathione-S-transferase and glutathione-reductase was not observed. (ii) The excretion of unmetabolized N-nitrosodimethylamine in rat urine during 24 h increased from 0.1% without pretreatment to 3.6% of the given dose on combination with a single dose of dithiocarbamate. (iii) The acute toxicity of NDMA could be reduced with diethanol-dithiocarbamate. After a single simultaneous application of the inhibitor with NDMA, the LD50 was increased from 40 to 66 mg/kg. When the sulfur compound was administered twice, both simultaneously and 24 h after the nitrosamine, lethality was almost completely inhibited. We conclude from these results that dithiocarbamates may be suitable compounds for chemoprevention of nitrosamine-induced tumors.
Frank
N
N
Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg.
Bertram
B
B
Scherf
H R
HR
Wiessler
M
M
D000818:Animals; D003640:Dealkylation; D004128:Dimethylnitrosamine / Q000378:metabolism* / Q000633:toxicity; D005978:Glutathione / Q000032:analysis; D005979:Glutathione Peroxidase / Q000032:analysis; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013859:Thiocarbamates / Q000494:pharmacology*
D013859:Thiocarbamates; D005979:Glutathione Peroxidase; D005978:Glutathione; D004128:Dimethylnitrosamine